Scientists have long sought the secrets of the 5-HT2A serotonin receptor—a central nervous system receptor that binds hallucinogenic compounds, including LSD and psilocybin. Many hope to discover why these molecules cause hallucinations when they bind to 5-HT2A while other compounds that bind to the receptor, including serotonin, do not. LSD and psilocybin have been shown to treat mood disorders such as depression, and scientists wonder if they can design molecules that maintain that mood-altering ability without causing hallucinations.
Researchers now report a structural biology–guided strategy for making such molecules. A team led by Sheng Wang of the Chinese Academy of Sciences and Jianjun Cheng of ShanghaiTech University determined the crystal structures of the 5-HT2A receptor bound to LSD, psilocin (the active form of psilocybin), serotonin, or lisuride, a nonhallucinogenic treatment for Parkinson’s disease. After visualizing the differences in how those molecules bind, the researchers then designed several compounds that they hypothesized would interact with 5-HT2A without inducing hallucinations (Science 2022, DOI: 10.1126/science.abl8615).
The team’s strategy was to design rigid molecules that would bind within a pocket of the 5-HT2A receptor and mimic one of two poses that serotonin and psilocin strike in the receptor. The researchers also wanted their molecules to avoid binding within a hydrophobic pocket because that interaction might spur hallucinations. Tests in mice suggest that two compounds, called IHCH-7079 and IHCH-7086, had antidepressant activity: mice given those compounds continued to struggle when suspended by their tails and swim when forced, unlike control mice, which gave up and exhibited depression-like behavior. IHCH-7079 and IHCH-7086 also didn’t appear to make the mice twitch their heads—behaviors that are observed when the rodents take LSD or psilocybin.
David E. Olson, a professor at the University of California, Davis, who is also working on making nonhallucinogenic psychoactive compounds, says this work adds to the growing evidence that analogs of psychedelics may be effective antidepressants. “The 5-HT2A receptor is one of the most important targets in neuropsychiatry. This additional structural data will aid efforts to design new antidepressants as well as antipsychotics,” he says in an email.
Wang says that the team’s compounds still need to be optimized, noting that their required effective dose in mice is high. Nevertheless, he says, “we definitely want to prove our concept in a clinical trial.”